July 13, 2007

Abstract We report a patient with combined polycystic ovary syndrome (PCOS) and autoimmune polyglandular syndrome (APS) type 2. A 26-year-old female presented with polyuria, polydipsia and acute weight loss. She was diagnosed with: (1) type 1 diabetes, with hyperglycemia, impaired insulin secretion, and positive autoantibodies for GAD-65 and IA-2; (2) autoimmune thyroiditis, with hypothyroidism, positive anti-microsomal and antithyroglobulin antibodies; and (3) PCOS, with hyperandrogenic signs that had developed 5 years earlier, amenorrhea for the previous 6 months, and characteristic multiple microcystic appearance of both ovaries on ultrasonography. She is being treated with multiple subcutaneous insulin injections, thyroxine replacement, and cyclic medroxyprogesterone for the aforementioned diseases, respectively. Although several investigations have reported a relationship between PCOS and the individual components of APS, this is the first report of both syndromes occurring simultaneously. Potential mechanisms for their interrelation and the possibility that PCOS is an autoimmune disease are discussed.

Polycystic ovary syndrome (PCOS), characterized by chronic anovulation and hyperandrogenism, is associated with several conditions arising from insulin resistance, such as type 2 diabetes. Autoimmune polyglandular syndrome (APS) should be considered when immune dysfunction affects two or more endocrine glands and other non-endocrine immune disorders are present. The components of APS type 2 include adrenal insufficiency, type 1 diabetes, hypothyroidism, Graves' disease, hypogonadism, vitiligo, alopecia and pernicious anemia. The association between these two disorders has recentiy been investigated. There have been several reports of PCOS occurring either with type 1 diabetes or autoimmune thyroiditis. However, there has been no report of APS type 2, involving both type 1 diabetes and autoimmune thyroiditis, in a patient with PCOS.

We report a 26-year-old female with PCOS, also suffering from APS type 2 that comprises type 1 diabetes and Hashimoto's thyroiditis, and review several papers.

Case report

A 26-year-old female presented with polyuria and polydipsia for the preceding 4 months and a weight loss of 4 kg over 1 month. She had been previously healthy and had no past medical history other than menstrual abnormalities. Since menarche at the age of 15 years her menstrual cycles had been irregular, with amenorrhea eventually developing 6 months before presentation, although this problem had not been evaluated. Hyperandrogenic signs such as acne and hirsutism had developed 5 years previously and progressed slowly since then. She also complained of diffuse hair loss, which had increased a month earlier. There was no family history of significant diseases, including diabetes.

When she was admitted her vital signs were stable, with alert mental status. She did not look ill and signs of dehydration were absent. Her body mass index (BMI) was 19 kg/m2 and her waist-to-hip ratio was 0.76 (waist 68 cm, hip 90 cm), indicating the absence of obesity. On physical examination, her thyroid gland was enlarged (approximately 40 g) and firmly palpable. Hyperandrogenic skin changes such as acne (moderate, according to the classification system of the American Academy of Dermatology) with seborrhea, hirsutism (modified Ferriman-Gallwey score 7) and diffuse alopecia (diagnosed as telogen effluvium) were observed. Acanthosis nigricans was not present.

Her fasting and postprandial blood sugar levels were 234 and 380 mg/dl, respectively, and glycated hemoglobin (HbAIc) was 17.3%. She was diagnosed with diabetes mellitus. On the basis of fasting and meal-stimulated C-peptide levels (0.11 and 0.14 ng/ml, respectively) and autoantibodies positive for glutamic acid decarboxylase (GAD)- 65 (43.5 U/ml; normal range,

A thyroid function test showed mild hypothyroidism, with triiodothyronine of 0.39 ng/ml (normal range, 0.78-1.82 ng/ml), free thyroxine of 0.80 ng/dl (normal range, 0.85-1.86 ng/dl) and thyroid- stimulating hormone of 4.61 mIU/1 (normal range, 0.17-4.05 mIU/1). Anti-microsomal antibody (1:25 600) and antithyroglobulin antibody (1:2560) were strongly positive, suggesting Hashimoto's thyroiditis. Findings on thyroid scanning (Figure IA) and ultrasonography (Figure IB) were also compatible with thyroiditis. Daily thyroxine (50 [mu]g) was prescribed and she is now in a euthyroid state. With evidence of type 1 diabetes and autoimmune thyroiditis, she was diagnosed with APS type 2. A rapid adrenocorticotropic hormone stimulation test was performed to rule out adrenal insufficiency, commonly found with APS type 2, although she had no suspicious symptoms. After an intravenous injection of 250 [mu]g of cosyntropin, her plasma Cortisol levels were 15.3, 23.2, 23.5 and 28.1 /ig/dl at 0, 30, 60 and 90 min, respectively. With the exclusion of adrenal insufficiency, she would have been classified into APS type 2b or type 3, according to previous definition [I].

Figure 1. (A) 99m-Tc scanning showed a moderately enlarged thyroid gland with increased and uneven uptake. (B) The thyroid ultrasonogram showed low and inhomogeneous parenchymal echogenecity with small, multiple nodules. These findings were consistent with Hashimoto's thyroiditis. (C) The pelvic ultrasonogram revealed multiple small follicles in both ovaries and increased volume with increased echogenecity in the ovarian stroma, which was consistent with polycystic ovary syndrome.

In evaluating the cause of die patient's amenorrhea, PCOS was initially suspected because of signs of androgen excess. The ultrasonographic findings were consistent with PCOS, showing more than 12 small follicles in both ovaries and an increased volume with increased echogenicity in the ovarian stroma (Figure IC). Hyperprolactinemia and congenital adrenal hyperplasia were excluded after measurement of prolactin (6.13 ng/ml; normal range, 2-26 ng/ ml) and early-morning 17-hydroxyprogesterone (1.16 ng/ml; normal range, 0.09-4.0 ng/ml). Cushing's syndrome and androgen-secreting tumor were also excluded by tests for 24-h urine free Cortisol (41.7 [mu]g/day; normal range,

Discussion

This case report presents a unique patient with PCOS and also suffering from APS type 2, comprising type 1 diabetes and Hashimoto's thyroiditis. Clinical hyperandrogenism, including hirsutism, acne and alopecia, combined with anovulation and polycystic ovary morphology led to a definite diagnosis of PCOS.

It is well known that the prevalence of impaired glucose tolerance and type 2 diabetes is significantly higher in patients with PCOS than in their unaffected counterparts, resulting from underlying insulin resistance, which is thought to be a main pathogenic feature of PCOS [5] . Besides type 2 diabetes, some investigators have observed that type 1 diabetes is also associated with PCOS. Escobar-Morreale and colleagues reported the high prevalence of PCOS (18.8%) in women with type 1 diabetes compared with the incidence in non-diabetic women [6], using the NIH 1990 diagnostic criteria. Using the revised 2003 Rotterdam consensus, which includes polycystic ovary morphology (PCOM) as a key element in the diagnostic triad [2], Codner and associates reported the frequencies of PCOS (40.5%) and PCOM (54.8%) in women with type 1 diabetes to be significantly higher than those in the control group [7]. The close association between type 1 diabetes and PCOS can be explained by hyperinsulinism. Because intensive insulin therapy is recommended for the strict metabolic control of type 1 diabetic patients, supraphysiological doses of insulin are used in a non- physiological way in many cases, leading to hyperinsulinism. Type 1 diabetic patients may also have underlying insulin resistance, aggravating this hyperinsulinism, especially in obese subjects [8]. Insulin plays a central role in androgen metabolism by enhancing the androgen production of theca cells synergistically with LH and by inhibiting the hepatic synthesis of sex hormone-binding globulin (SHBG), thus increasing the proportion of free testosterone [9] . However, the synthesis and secretion of SHBG, which is suppressed by the insulin delivered into the portal circulation, is not reduced by exogenous hyperinsulinism [10]. A recent study demonstrated a threefold higher prevalence of autoimmune thyroiditis in patients with PCOS [H]. As both conditions are clustered in families, a common genetic defect may be suspected, although it has not yet been found. An increase in the estrogen-to-progesterone ratio is thought to be one of the most important causes, because estrogen enhances humoral immunity, thus promoting B-cell-mediated autoimmune diseases, whereas progesterone plays a protective role as a natural immune suppressor [12,13]. The depletion of progesterone resulting from anovulatory cycles in patients with PCOS may stimulate die immune system, leading to autoimmune thyroiditis. Therefore, the restoration of the ovulatory cycle would be an appropriate strategy to prevent autoimmune thyroiditis in patients with PCOS. Once hypothyroidism develops, it can aggravate PCOS by increasing the conversion of androstenedione to testosterone and its aromatization to estradiol, and by reducing the metabolic clearance rates of androstenedione and estrone [14].

Whether an autoimmune reaction contributes to the development of PCOS is still contentious. Some reports indicate that autoantibodies to steroid-producing cells and to their specific enzymes are closely related to ovarian failure and infertility in patients with autoimmune diseases [15]. In some cases of PCOS, autoimmune disturbances have been demonstrated, with high concentrations of antiovarian antibodies [16,17], although disagreement exists about whether the autoimmune mechanism is of prime importance [18]. A study by an Estonian group revealed that one or more common autoantibodies were detected in 40.7% of female patients with reproductive failure. Antinuclear antibody and anti-smooth muscle antibody were the most frequent autoantibodies in patients with PCOS, presenting another potential autoimmune mechanism [19].

Clinical and/or biochemical evidence of hyperandrogenism is an important feature of patients with PCOS. Hirsutism is thought to be the primary clinical indicator of androgen excess, whereas the presence of acne is less prevalent. The prevalence of androgenic alopecia in PCOS is still unclear, but Cela and co-workers reported the prevalence of PCOS to be as high as 67% in women witii androgenic alopecia [20] . A considerable proportion of patients with PCOS may demonstrate elevated circulating androgen levels, especially free testosterone, whereas 20-40% will have androgen levels within the normal range, although the inaccuracy and variability of the laboratory measurements should be considered. Our patient is an example of clinical hyperandrogenism without biochemical hyperandrogenemia. This is probably due to increased local tissue sensitivity to circulating androgens or ethnic differences in the phenotypic expression of peripheral androgen excess [21]. Alopecia is associated with both PCOS and APS type 2, although its pathogenesis and manifestations are somewhat different. It is a minor component of APS with an immunological mechanism, and in some cases tyrosine hydroxylase is recognized as the relevant autoantigen [22]. Telogen effluvium was diagnosed in our patient, which is thought to be a sign of early androgenic alopecia, although there is a possible link to hypothyroidism. Treatment measures for hyperandrogenism include weight reduction, oral contraceptives, antiandrogens (spironolactone, cyproterone acetate), insulin sensitizers (metformin, thiazolidinedione), etc. Medroxyprogesterone acetate is another option because it directly affects the hypothalamicpituitary axis by decreasing gonadotropin-releasing hormone production and the release of gonadotropins, thereby reducing testosterone and estrogen production by the ovary [23] .

Hyperandrogenic type 1 diabetic patients have several characteristics that differ from those of nondiabetic patients [7,24,25]. As in our patient, a relatively small increase in the LH/ FSH ratio is observed, which reflects ovarian hyperandrogenism in women with type 1 diabetes. Normal serum SHBG levels might reduce the delivery of androgen to the tissues. This prevents androgen excess in patients with type 1 diabetes, resulting in relatively low hirsutism scores.

To our knowledge, there has been no report of patients with PCOS and APS simultaneously. In our patient, it was difficult to define whether PCOS influenced APS type 2 or vice versa, because both were diagnosed at the same time. Because she had never used insulin before, it is hard to infer that PCOS was the result of exogenous hyperinsulinism. Other pathogenic mechanisms, such as insulin resistance, increased fat mass and abnormalities in the growth hormone/insulin-like growth factor-I axis, could have contributed to the relationship between PCOS and type 1 diabetes, although her low BMI and lack of metabolic syndrome lessen this possibility. It is unclear whether Hashimoto's thyroiditis is influenced by PCOS.

The interrelation between die components of APS and PCOS, as in our patient, suggests that patients with PCOS may possibly have APS synchronously. It would be reasonable to screen for components of APS, especially type 1 diabetes and autoimmune thyroiditis, if clinically warranted. However, the precise mechanism of the association between APS and PCOS remains to be elucidated.

1 Division of Endocrinology and Metabolism, Department of Internal Medicine, The Catholic University of Korea, Seoul, South Korea, and 2 Department of Obstetrics and Gynecology, The Catholic University of Korea, Seoul, South Korea